Functionalized chelants, or bifunctional coordinators, are known to be capable of being covalently attached to an antibody having specificity for cancer or tumor cell epitopes or antigens. Radionuclide complexes of such antibody/chelant conjugates are useful in diagnostic and/or therapeutic applications as a means of conveying the radionuclide to a cancer or tumor cell. See, for example, Meares et al., Anal. Biochem., 142, pp. 68-78, (1984); and Krejcarek et al., Biochem. and Biophys. Res. Comm., 77, pp. 581-585 (1977).
The methodology taught in the art to prepare such complexes involves treatment of an antibody/chelant conjugate with an excess of radionuclide to form a complex followed by purification of the complex. A major disadvantage of such methodology is that the radionuclide (a lanthanide or transition metal) must be kinetically labile in order to be rapidly sequestered by the antibody/chelant conjugate. This feature is disadvantageous in that the kinetic lability (or substitution lability)leads to problems associated with the serum stability of the complex. That is, the radionuclide readily dissociates from the complex in the presence of serum. Poor serum stability of such complexes leads to diminished therapeutic and/or diagnostic (imaging) effectiveness and poses a greater potential for general radiation damage to normal tissue [Cole et al., J. Nucl. Med., 28, 83-90 (1987)]. More specifically, serum stability has been shown to be a problem with complexes containing .sup.67 Cu, .sup.90 Y, .sup.57 Co, and .sup.111 In [Brechbeil et al., Inorg. Chem., 25, 2772-2781 (1986)].
Another disadvantage associated with the use of labile radionuclides for antibody labelling is that substitutionally labile trace metals (which are not radioactive) are frequently incorporated into the chelant. Competition for such non-active trace metals diminishes the biological efficacy of the antibody/chelate complex since, inter alia, a lower quantity of radionuclide is delivered to the target site.
The majority of bifunctional coordinators or functionalized chelants which have been taught in the art to sequester radionuclides are carboxymethylated amine derivatives such as functionalized forms of ethylenediaminetetraacetic acid (EDTA) (U.S. Pat. No. 4,622,420) or diethylenetriaminepentaacetic acid (DTPA) (U.S. Pat. Nos. 4,479,930 and 4,454,106). In U.S. Pat. No. 4,622,420 it is generally taught that EDTA derivatives can also sequester ionic species of rhodium. However, rhodium, particularly rhodium (III), is known to be a substitution inert transition metal and it is further known that extreme conditions of temperature and duration are required to form its EDTA complex (Dwyer et al., J. Amer. Chem. Soc., 83, pp. 4823-4826 (1960)). In addition, it has been reported that ethylenediaminedisuccinic acid will not form complexes with rhodium (III) at any pH below temperatures of 100.degree. C. (J. A. Neal and N. J. Rose, Inorg. Chem., 12, 1226-1232 (1972)).
Tetraaza chelants (Troutner et al., J. Nucl. Med., 21, pp. 443-448 (1980)) and alkylene amine oximes (U.S. Pat. No. 4,615,876) have been used to sequester .sup.99m Tc, an isotope with nuclear properties suitable for diagnostic work only.
Rhodium-105 is both a gamma emitter (suitable for diagnostic work) and a short half-life beta emitter (suitable for therapeutic work). Because rhodium-105 can be used for both diagnostics and therapy, and because rhodium is substitution inert, it would be highly desirable to have functionalized chelants capable of forming complexes with radioactive rhodium that can be attached to an antibody. Tetraaza complexes of naturally occurring rhodium (III) are known in the literature for both linear (e.g., Bosnich et al., J. Chem. Soc. Sec. A, pp. 1331-1339 (1966)) and macrocyclic (E. J. Bounsall and S. R. Koprich, Canadian Journal of Chemistry, 48(10), pp. 1481-1491 (1970)) amines, however, functionalized polyaza chelants suitable for complexing radioactive rhodium and subsequent attachment to an antibody have been heretofore unknown.